The skin serves numerous functions but its primary function is as a protective layer or barrier. The most important role of the skin for terrestrial animals is to protect the water-rich internal organs from the dry environment. This cutaneous barrier function of the skin resides in the upper most thin layer (approximately 10-20 μm in humans) called stratum corneum. The water impermeability of this layer is 1000 times-high than that of other membranes of living organisms. Potts & Francoeur (1991) J. Invest. Dermatol. 96;495-499.
The stratum corneum is composed of two components, i.e., protein-rich nonviable cells and intercellular lipid domains. Elias et al. (1993) Curr. Opin. Dermatol. 231-237. The lipid molecule in the intercellular domain form a bilayer structure. The water impermeability is due to the conformation of the lipid molecules and also the order of the deal cells. Denda et al. (1994) Arch. Dermatol. Res. 286:41-46. Because of this specific “brick and mortar” structure, the stratum corneum shows high water impermeability.
The uppermost layer of the skin, called epidermis, is mainly constructed of keratinocytes. The epidermis is in a constant state of self-replacement. At the bottom layer, keratinocyte stem cells divide into daughter cells, which are displaced outward, and which differentiate through successive overlying layers to enter the stratum corneum. Then, the keratinocytes die (apoptosis) and their cellular organella and cytoplasm disappear during the final process of differentiation. Intercellular lipids are primarily generated from exocytosis of lipid-containing granules called lamellar bodies, during the terminal differentiation. The secreted lipids spread over the intercellular domains and form a bilayer structure. Elias et al. (1993), supra.
Ionic signals play important role in the homestatic mechanim of the epidermal barrier function. Lee et al. (1992) J. Clin. Invest. 89:530-538. In normal skin, calcium is localized with high concentration in the epidermal granular layer, i.e., the uppermost layer of the epidermis, just below the stratum corneum. On the contrary, the concentration potassium is the highest in the spinous layer, i.e., middle of the epidermis, and the lowest in the granular layer.
Calcium is a universal messenger, even in simple organisms and plants. The combination of its ionic radius and double charge may allow it tighter binding to receptors to the exclusion of other ions such as magnesium, leading to strong, specific binding. Carafoli & Penniston (1985) The Calcium Signal. Sci. Am. 253:70-78. The specificity enables cells to form special receptors to assess signals from calcium. For many parts of the body, Ca2+ often acts as a second messenger in a manner similar to cAMP. In skin, calcium can provide signals for the cells, either extracellular or intracellular (in the cytosol). The extra- and intracellular signaling may be connected to each other, but may also act separately. It has been found that intracellular Ca2+ increases with raised extracellular Ca2+. This implies that increased intracellular Ca2+ is the actual signal to trigger keratinocytes differentiation. Tanojo & Maibach (1999) in Percutaneous Absorption, 3rd Ed., Bronaugh & Maibach, ed., Marcel Dekker, NY, pp. 939-950.
As Ca2+ cannot be metabolized like other second-messenger molecules, cells tightly regulate intracelular levels thorough numerous binding and specialized extrusion proteins. Clapham (1995) Cell 80:259-268. The concentration of calcium in extracellular spaces (generally ˜1.5 mM) is four orders of magnitude higher than in the cytosol (˜0.1 μM). In excitable cells, for example, muscle cells, the extracellular concentration of calcium must be closely regulated to keep it at its normal level of ˜1.5 mM, so that it cannot accidentally trigger the muscle contraction, the transmission of nerve impulses, and blood clotting. In other cells, including keratinocytes, the extracellular level is maintained in a specific equilibrium with the intracellular concentrations.
As described above, there is a high calcium gradient between extra- and intracellular domains of keratinocytes, which requires tight regulation. Moreover, a calcium gradient is present within the epidermis, with higher quantities of Ca2+ in the upper than the lower epidermis. Menon et al. (1985) J. Invest. Dermatol. 102:789-795. Ca2+ concentration increases steadily from the basal region to stratum corneum, which this is not the case with other ions. Forslind et al (1995) Scanning Microsc. 9:1011-1026. Such a gradient is not observed in skin abnormalities related to the formation of abnormal barrier function, such as psoriasis. Menon & Elias (1991) Arch. Dermatol. 127:57-63. It has been reported that disruption of the skin barrier with acetone treatment or tape stripping depletes Ca2+ from the upper epidermis, resulting in the loss of the Ca2+ gradient. This is due to accelerated water transit that leads to the increased passive loss of Ca2+ into and through the stratum corneum. Mao-Qiang et al. (1997) Exp. Dermatol. 6:36-40.
In summary, calcium ions play an important role in the homeostasis of skin barrier. A change in the barrier will change the calcium ion gradient in skin and lead to barrier repair process. A severe change might lead to a high degree of calcium signaling, which may induce the activation of various processes, from increased synthesis of skin components or messengers to the inflammatory reactions. Thus, there exists a need for compositions and methods for activating the barrier repair process to restore normal barrier function to skin adversely affected by environmental elements or pathological conditions.